The majority of our transient bugs on WordPress.com are probably related to APC opcode issues. We try to catch them and handle it gracefully, but it isn't always so easy.
I'm interested to hear what versions of PHP and APC you used.
In my experience, stable APC releases have been very stable, but beta APC can poop out pretty bad, even if the changelog doesn't indicate anything that might affect your application.
I've used stable APC + PHP + Apache releases to do some large things, so not sure why APC is an utter bomb in 2012.
No kidding. There really aren't "three major opcode caches" anymore, APC won out years ago and is now tightly integrated with PHP compiles and as a module available in any package manager.
It's worth revisiting. We had huge problems with it when we tried it out in 2007, but I tried it again earlier this year and was pleasantly surprised - I got everything working, easily, and nothing broke. And I got that speed up.
My gut feeling tells me that your profiling is correct, however - any significant PHP application (that isn't written terribly inefficiently) will have its bottleneck in data access and not the parse/compile stage. There's very little point to speeding up by 250% a portion of your app that only accounts for 2% of execution time!
I'd be interested to read on your blog about what APC problems you've encountered - we have many wp installs with APC and the only problem is it will segfault once in a blue moon but we can automatically restart when that happens.